P765: UPDATED ENROLLMENT AND RESULTS FROM THE PHASE 1 SUBSTUDY OF IVOSIDENIB IN PATIENTS WITH IDH1-MUTANT RELAPSED/REFRACTORY MYELODYSPLASTIC SYNDROME (R/R MDS)
Authors: C. D. DiNardo, J. M. Foran, J. M. Watts, E. M. Stein, S. de Botton, A. T. Fathi, G. T. Prince, R. M. Stone, P. A. Patel, G. J. Roboz, M. L. Arellano, H. P. Erba, A. Pigneux, P. Baratam, R. K. Stuart, X. Thomas, I. R. Lemieux, X. Bai, S. M. Kapsalis, G. Garcia-Manero, D. A. Sallman
Journal: HemaSphere (2022)

Background: Isocitrate dehydrogenase 1 (IDH1) is mutated in ~3% of patients with MDS, increasing the risk of transformation to acute myeloid leukemia (AML). Ivosidenib (IVO), an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, is FDA approved for mIDH1 R/R AML and mIDH1 newly diagnosed AML in patients ≥75 years old or with comorbidities precluding the use of intensive induction chemotherapy. Promising safety and efficacy findings in the first-in-human, open-label, dose escalation and expansion study of IVO in patients with mIDH1 advanced hematologic malignancies (NCT02074839) led to the FDA granting Breakthrough Therapy designation to IVO in mIDH1 MDS. 12 patients with R/R MDS received IVO 500 mg once daily (QD). Median age was 72.5 (range 52–78) years and all had received prior MDS treatment. The investigator-assessed overall response rate (ORR) was 75%, with median response duration of 21.4 months. This substudy enrolled additional patients with mIDH1 R/R MDS; therefore, we report updated results. Aims: To further evaluate safety, tolerability, clinical activity, and pharmacokinetics/pharmacodynamics of IVO in patients with mIDH1 R/R MDS. Methods: This substudy of the single-arm study of IVO evaluated patients with mIDH1 R/R MDS after documented failure or relapse following prior standard therapy including intensive chemotherapy and hypomethylating agents. Patients must have given informed consent, have high disease burden based on IPSS or IPSS-R risk at baseline, and an Eastern Cooperative Oncology Group performance status score of 0–2. IVO 500 mg QD was given orally on days 1–28 of 28-day cycles. Results: As of 08May2021, 16 patients with R/R MDS were enrolled: 3 of the 16 who received 500 mg IVO QD were women; median age was 73.5 (range 52–78) years and 44% were ≥75 years of age. As of the data cut, 5 (31%) patients remained on treatment and free from leukemic transformation and 11 (69%) had discontinued including 6 for disease progression, 1 for allogeneic stem cell transplantation, and 1 owing to an adverse event (AE) of sepsis (the only fatal AE; reported by investigator as not related to IVO). Differentiation syndrome was observed in 2 patients (grade 2). Electrocardiogram QT prolonged was reported in 2 patients (grade 1 and 2). The Table outlines AEs. Complete response (CR) was achieved by 7 of 16 patients (44%; 95% CI, 20%, 70%), partial response (PR) by 1 (6%), and marrow CR by 5 (31%), giving an ORR of 81% (95% CI, 54%, 96%). At 12 months, the Kaplan-Meier estimate of duration of CR+PR was 60.0%. 3 patients experienced CRs lasting 24.0, 63.7, and 65.4 months, which remain ongoing. 11 of 16 (69%) patients achieved hematologic improvement in ≥1 lineage. Among 7 patients who were transfusion dependent at baseline, 5 (71%) became independent of red blood cell or platelet transfusions for 56 or more consecutive days on treatment. Further translational data are being processed. Image:Summary/Conclusion: IVO monotherapy induced durable remissions and transfusion independence in patients with mIDH1 R/R MDS, with a manageable safety profile. These results contribute to IVO’s potential as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS.